Human mesenchymal stem cells/multipotent stromal cells (MSCs) hold great promise in aiding wound healing through their ability to modulate all phases of repair and regeneration, most notably their secretion of pro-regenerative paracrine factors. However, MSC clinical utility is hindered by poor survival rates post-transplantation due to the harsh microenvironment in injured tissue. Previous work has shown that the matricellular protein Tenascin-C (TNC) provides survival signaling to MSCs via the epidermal growth factor receptor by restricting its activation at the plasma membrane, resulting in enhanced prosurvival signals. Herein, we investigate how TNC influences MSC survival and MSC-mediated promotion of the wound healing process. This study examined the survival and angiogenic potential of MSCs cultured on TNC-coated surfaces under ischemic duress in vitro. We also assessed the angiogenic and wound healing outcomes of MSC + TNC in vivo using a CXCR3−/− mouse model that exhibits a delayed healing phenotype within the tissue replacement phase of repair. We found that MSCs in the presence of TNC exhibit higher levels of angiogenic-promoting processes, collagen maturation, and an overall better wound healing outcome than MSCs administered alone. This was seen in vitro in terms of enhanced tube formation. In vivo, the MSCs in the presence of TNC stabilized with a coacervate delivery system resulted in more regenerative wounds with accelerated maturation of the dermis. These findings suggest the coupling of TNC to MSCs as a promising tool for future MSC-ECM combinatorial therapies for wound healing applications.

中文翻译：

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基质细胞蛋白 Tenascin-C 在缺血条件下增强间充质干细胞血管生成和伤口愈合功效

人间充质干细胞/多能基质细胞 (MSC) 通过调节修复和再生的所有阶段的能力，尤其是促再生旁分泌因子的分泌，在帮助伤口愈合方面大有可为。然而，由于受损组织中恶劣的微环境，移植后存活率低，阻碍了 MSC 的临床应用。先前的研究表明，基质细胞蛋白 Tenascin-C (TNC) 通过表皮生长因子受体通过限制其在质膜上的激活向 MSC 提供生存信号，从而增强促生存信号。在此，我们研究 TNC 如何影响 MSC 存活和 MSC 介导的伤口愈合过程促进。本研究检测了在体外缺血胁迫下在 TNC 涂层表面上培养的 MSCs 的存活率和血管生成潜力。我们还使用 CXCR3−/− 小鼠模型评估了 MSC + TNC 在体内的血管生成和伤口愈合结果，该模型在组织置换修复阶段表现出延迟愈合表型。我们发现，与单独使用 MSCs 相比，存在 TNC 的 MSCs 表现出更高水平的血管生成促进过程、胶原蛋白成熟和总体上更好的伤口愈合结果。这在增强的管形成方面在体外被观察到。在体内，在 TNC 存在的情况下，MSCs 用凝聚层输送系统稳定，导致更多的再生伤口，加速真皮成熟。